This invention relates to a novel process for preparing N-substituted 2-sulfinylimidazoles compounds.
2-Sulfanylimidazoles are important heterocycles that are used in a number of pharmaceutical drugs or drug candidates. For example, both a GPIIB-IIIA antagonist OPC-29030 (Chem. Pharm. Bull. 43(10), 1724 (1995); CAS RNS: 161190-39-2) and an antiulcer agent T-330 (CSA RNS: 52410-51-2) which are in clinical trials contain an N-aryl 2-sulfanylimidazole substructure. On the other hand, a series of 4,5-unsubstituted 2-sulfanylimidazoles are described as potent inhibitors of the acid secretory enzyme H+/K+-ATPase (Yamada, M. et al.; J. Med. Chem. 39, 596 (1996)). These 2-sulfanylimidazoles are generally prepared from imidazole-2-thiones or imidazoles through alkylation with alkyl halides or activated aryl halides in the presence of bases. Either approach requires stepwise preparation and isolation of the respective intermediates. Furthermore, imidazole-2-thiones are typically synthesized from a thiourea acetal intermediate via an acid-catalyzed cyclization (Hofmann, K. in xe2x80x9cThe Chemistry of Heterocyclic Compoundsxe2x80x9d, eds. By A. Weissberger, Interscience Publishers Inc., New York, 1953, p86-87; Elslager, E. F. et al., J. Heterocyclic Chem. 17, 129 (1980)). The reactions mentioned above were conducted under either strongly acidic or basic conditions which are incompatible with many functional groups.
The inventors have developed a convenient one step synthesis of N-substituted 2-sulfanylimidazole compounds without using a base or an acid, thus allowing for functional groups that would otherwise be incompatible with such a reaction.
This invention relates to a process for preparing an N-substituted 2-sulfanylimidazole compound of the formula (I) 
by reacting an isothiocyanate of the formula R1NCS with an xcex1-aminocarbonyl compound of the formula NH2CHR4C(OP)2R3 and an alkyl halide or an activated aryl halide of the formula R2X in a solvent, alternatively, by reacting an isothiocyanate of the formula R1NCS with an xcex1-aminocarbonyl compound of the formula NH2CHR4C(OP)2R3 before adding an alkyl halide or an activated aryl halide of the formula R2X, wherein R1 and R2 independently represent alkyl, heterocyclyl, aryl, or heteroaryl groups; R3 and R4 independently represent hydrogen, alkyl, heterocyclyl, aryl or heteroaryl or may form a non-aromatic ring; P represents a protecting group of a carbonyl group.
Preferably, R1 represents aryl or heteroaryl. Preferably, R2 represents alkyl. Preferably, R3 represents hydrogen. Preferably, R4 represents hydrogen. Preferably, said halide is chloride, bromide or iodide. Preferably, the protecting group of the carbonyl group of xcex1-aminocarbonyl is dialkyl or cyclic alkyl acetal.
This invention relates to a convenient one step synthesis of N-substituted 2-sulfanylimidazole from an isothiocyanate, an xcex1-aminocarbonyl compound and an alkyl halide or an activated aryl halide. Reaction of an isothiocyanate with an xcex1-aminocarbonyl compound affords a thiourea acetal intermediate, which without isolation or purification provides the desired N-substituted 2-sulfanylimidazole upon treatment with an alkyl halide.
The detailed description of the invention which follows is not intended to be exhaustive or to limit the invention to the precise details or examples disclosed. Details and examples have been chosen to explain the invention to others skilled in the art.
The processes of this invention described herein and in the claims, may be performed in s veral ways. Preferred methodologies are described as follows.
This invention provides a process for preparing an N-substituted 2-sulfanylimidazole compound of the formula (I) 
by reacting an isothiocyanate of the formula R1NCS with an xcex1-aminocarbonyl compound of the formula NH2CHR4C(OP)2R3 and an alkyl halide or an activated aryl halide of the formula R2X in a solvent, alternatively, by reacting an isothiocyanate of the formula R1NCS with an xcex1-aminocarbonyl compound of the formula NH2CHR4C(OP)2R3 before adding an alkyl halide of the formula R2X, wherein R1 and R2 independently represent alkyl, heterocyclyl, aryl, or heteroaryl groups; R3 and R4 independently represent hydrogen, alkyl, heterocyclyl, aryl or heteroaryl or may form a non-aromatic ring; P represents a protecting group of a carbonyl group.
Preferably, R1 represents aryl or heteroaryl. Preferably, R2 represents alkyl. Preferably, R3 represents hydrogen. Preferably, R4 represents hydrogen. Preferably, said halide is chloride, bromide or iodide. Preferably, the protecting group of the carbonyl group of xcex1-aminocarbonyl is dialkyl or cyclic alkyl acetal.
The reaction is performed by mixing all reactants, i.e., an isothiocyanate of the formula R1NCS, an xcex1-aminocarbonyl compound of the formula NH2CHR4C(OP)2R3 and an alkyl halide of the formula R2X in a solvent. Alternatively, an isothiocyanate of the formula R1NCS is reacted with a protected xcex1-aminocarbonyl compound of the formula NH2CHR4C(OP)2R3 in a solvent to provide a thiourea intermediate. There is no restriction on the solvent used in this reaction. The reaction can be conducted in either organic or inorganic solvents. Preferably, the solvents used in the invention are organic solvents. More preferably, the reaction is conducted in an organic solvent, such as toluene or ethanol. Subsequently, the thiourea intermediate is reacted with an alkyl halide to provide the desired N-substituted 2-sulfanylimidazole compound. Preferably, the reaction is conducted under sealed condition. Preferably, alcohol solvent is added along with an alkyl halide or an activated aryl halide. Preferably, the reaction is conducted at elevated temperature aftermixing all reactants. More preferably, the reaction is heated to 60-80xc2x0 C. from room temperature. The reaction is useful for a large scale production of N-substituted 2-sulfanylimidazoles. This invention is useful for preparing important pharmaceutical agents such as drugs or drug candidates which contain N-substituted 2-sulfanylimidazoles.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cActivated aryl halidexe2x80x9d, as used herein, means an aryl halide that is substituted by some type of substituents that activate the aryl halide so that it can be reacted with thiourea intermediate to form the desired N-substituted 2-sulfanylimidazole. Substituents used for activation of an aryl halide are electron-withdrawing groups.
xe2x80x9cAlkylxe2x80x9d, as used herein, means a cyclic, branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, cyano, nitro, hydroxyl, mercapto, carboxy, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing xe2x80x94Cxe2x95x90Cxe2x80x94 or xe2x80x94Cxe2x95x90Cxe2x80x94 subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 1 to 8 carbon atoms.
xe2x80x9cArylxe2x80x9d, as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can be optionally unsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
xe2x80x9cElectron-withdrawing groupxe2x80x9d, as used herein, means a specific group that makes the electron density of the parent molecule unevenly distributed when it is attached to the parent molecule. An electron-withdrawing group pulls the electron from the parent molecule toward this group. An electron-withdrawing group includes but not limited to a nitro, cyano or trifluoromethyl group. More examples of electron-withdrawing groups can be found in March, Advanced Organic Chemistry, 4th, Wiley Interscience, 1992.
xe2x80x9cElevated temperaturexe2x80x9d, as used herein, means the reaction is conducted at a temperature that is higher than room temperature. The reaction in the invention is conducted at a temperature ranging from 60 to 80xc2x0 C. after all the reactants are added.
xe2x80x9cHaloxe2x80x9d, as used herein, means chloro, bromo or iodo atoms in the invention. The fluorine atom is excluded in the invention. A compound containing halo atom is referred as a halide.
xe2x80x9cHeteroarylxe2x80x9d, as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., pyrridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) and having at least one hetero atom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, halo, mercapto, and other substituents.
xe2x80x9cHeterocyclylxe2x80x9d, as used herein, means radical heterocycles which are saturated, or unsaturated and non-aromatic. These may be substituted or unsubstituted, and are attached to the core structure via any available valence, preferably any available carbon. More preferred heterocycles are of 5 or 6 members. In six membered non-aromatic monocyclic heterocycles, the heteroatom(s) are from one to three Ns, and wherein when the heterocycle is five membered and non-aromatic, preferably it has one or two heteroatoms selected from O, N, or S.
xe2x80x9cLarge scalexe2x80x9d, as used herein, means that the reaction provides the desired product in an industrial scale or in a large quantity. The reaction in the invention can be used either to produce a picogram, milligram, or gram quantity or to produce on the kilogram or tons scale.
xe2x80x9cProtecting groupxe2x80x9d, as used herein, means a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) generated in such protected reactions. Most wildly used protecting group for a carbonyl functionality is acetal (or ketal). Examples of more protecting groups can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed. John Wiley and Sons, (1991).
xe2x80x9cSealed conditionxe2x80x9d, as herein used, means that the reaction is conducted in a container that is not exposed to air directly. Any isolated system that is not exposed directly to air is a sealed system. For example, the reactions performed in a sealed tube or in a capped container or under argon or other inert gas atmosphere are considered to be under sealed condition.
xe2x80x9cSolventxe2x80x9d, as herein used, means a liquid that can dissolve another compound and has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include alcohols (methanol, 1-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol, etc.), hydrocarbons (benzene, toluene, etc.), amides (dimethyl acetamide, dimethylformamide, etc.), halides (dichloroethane, dichloroiethane, etc.), and ethers (tetrahydrofuran, dioxane, etc.). Other solvents include water, 1-methyl-2-pyrrolidine, diethyl phosphite, tetramethaylsulphone, dimethyl sulphoxide, acetonitrile and pyridine.
The following abbreviations have the indicated meanings:
Bn=benzyl
CDCl3=deutered chloroform
CH2Cl2=dichloromethane
ESIMS=electron spray mass spectrometry
EtOAc=ethyl acetate
EtOH=ethanol
Ph=phenyl
TLC=thin layer chromatography
Me=methyl
Et=ethyl
n-Bu=normal butyl
t-Bu=tertiary butyl